RSV-Induced H3K4 Demethylase KDM5B Leads to Regulation of Dendritic Cell-Derived Innate Cytokines and Exacerbates Pathogenesis In Vivo.

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  • Additional Information
    • Source:
      Publisher: Public Library of Science Country of Publication: United States NLM ID: 101238921 Publication Model: eCollection Cited Medium: Internet ISSN: 1553-7374 (Electronic) Linking ISSN: 15537366 NLM ISO Abbreviation: PLoS Pathog Subsets: MEDLINE
    • Publication Information:
      Original Publication: San Francisco, CA : Public Library of Science, c2005-
    • Subject Terms:
      Cytokines/*biosynthesis ; DNA-Binding Proteins/*immunology ; Dendritic Cells/*immunology ; Gene Expression Regulation/*immunology ; Jumonji Domain-Containing Histone Demethylases/*immunology ; Respiratory Syncytial Virus Infections/*immunology; Animals ; CD4-Positive T-Lymphocytes/immunology ; Cells, Cultured ; Chromatin Immunoprecipitation ; Coculture Techniques ; Cytokines/immunology ; Disease Models, Animal ; Immunity, Innate/immunology ; Mice ; Mice, Inbred C57BL ; Mice, Transgenic ; RNA, Small Interfering ; Real-Time Polymerase Chain Reaction ; Respiratory Syncytial Viruses/immunology ; Transfection
    • Abstract:
      Respiratory syncytial virus (RSV) infection can result in severe disease partially due to its ability to interfere with the initiation of Th1 responses targeting the production of type I interferons (IFN) and promoting a Th2 immune environment. Epigenetic modulation of gene transcription has been shown to be important in regulating inflammatory pathways. RSV-infected bone marrow-derived DCs (BMDCs) upregulated expression of Kdm5b/Jarid1b H3K4 demethylase. Kdm5b-specific siRNA inhibition in BMDC led to a 10-fold increase in IFN-β as well as increases in IL-6 and TNF-α compared to control-transfected cells. The generation of Kdm5bfl/fl-CD11c-Cre+ mice recapitulated the latter results during in vitro DC activation showing innate cytokine modulation. In vivo, infection of Kdm5bfl/fl-CD11c-Cre+ mice with RSV resulted in higher production of IFN-γ and reduced IL-4 and IL-5 compared to littermate controls, with significantly decreased inflammation, IL-13, and mucus production in the lungs. Sensitization with RSV-infected DCs into the airways of naïve mice led to an exacerbated response when mice were challenged with live RSV infection. When Kdm5b was blocked in DCs with siRNA or DCs from Kdm5bfl/fl-CD11c-CRE mice were used, the exacerbated response was abrogated. Importantly, human monocyte-derived DCs treated with a chemical inhibitor for KDM5B resulted in increased innate cytokine levels as well as elicited decreased Th2 cytokines when co-cultured with RSV reactivated CD4+ T cells. These results suggest that KDM5B acts to repress type I IFN and other innate cytokines to promote an altered immune response following RSV infection that contributes to development of chronic disease.
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    • Grant Information:
      R01 AI036302 United States AI NIAID NIH HHS; R01 HL112897 United States HL NHLBI NIH HHS; R01AI036302 United States AI NIAID NIH HHS
    • Accession Number:
      0 (Cytokines)
      0 (DNA-Binding Proteins)
      0 (RNA, Small Interfering)
      EC 1.14.11.- (Jumonji Domain-Containing Histone Demethylases)
      EC 1.14.11.- (Kdm5b protein, mouse)
    • Publication Date:
      Date Created: 20150618 Date Completed: 20160404 Latest Revision: 20181113
    • Publication Date:
      20231215
    • Accession Number:
      PMC4470918
    • Accession Number:
      10.1371/journal.ppat.1004978
    • Accession Number:
      26083387